Loss of Adrenergic Augmentation of Diastolic Intra-LV Pressure Difference in Patients With Diastolic Dysfunction

Ohara, Takahiro; Niebel, Cassie L.; Stewart, Kelley C.; Charonko, John; Pu, Min; Vlachos, Pavlos P.; Little, William C.

doi:10.1016/j.jcmg.2012.05.013

Cited by 58 publications

(49 citation statements)

References 38 publications

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“…The current study enrolled subjects with an earlier stage of HFpEF, where filling pressures were closer to normal at rest and physical examination evidence of congestion was largely absent. Despite the absence of right-sided structural remodeling, RV systolic and diastolic function were significantly impaired in the HFpEF group, differences that became more evident in the setting of β-stimulation, similar to prior studies evaluating LV-systemic arterial reserve with adrenergic stimulation [9][10][11][12][13] or exercise stress. 36,37 In HFpEF subjects, tricuspid annular s′ increased with dobutamine in relation to afterload reduction from dobutamine rather than an increase in contractility, which would manifest by an upward shift in the s′ versus PA pressure relationship.…”

Section: Rv Dysfunction and Rv-pa Coupling In Hfpefsupporting

confidence: 76%

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right Ventricular

Andersen

Hwang

Kane

et al. 2015

Circ: Heart Failure

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Acute stress responses in the cardiovascular system are mediated predominantly though the autonomic nervous system. 8 Previous studies have shown that LV-systemic arterial responses to β-adrenergic stimulation are depressed in patients with HFpEF. Background-Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV-pulmonary artery (PA) functional reserve responses and RV-PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results-In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV dP/dt max /IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure-flow relationship when compared with controls (all P<0.001). RV-PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions-Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01418248.(Circ Heart Fail. 2015;8:542-550.

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Section: Rv Dysfunction and Rv-pa Coupling In Hfpefsupporting

confidence: 76%

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right Ventricular

Andersen

Hwang

Kane

et al. 2015

Circ: Heart Failure

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“…Loss of this response impacts the capacity to enhance early filling as the diastolic interval shortens during exercise or adrenergic challenge. In patients with diastolic dysfunction, augmentation of the atrialapical LV pressure gradient during dobutamine infusion was reduced, with greatest impairment in patients with mild dysfunction (23). The prolongation of IVRT c during dobutamine suggests that SHRs recapitulate this aspect of clinical diastolic dysfunction.…”

Section: Discussionmentioning

confidence: 94%

Ranolazine improves diastolic function in spontaneously hypertensive rats

Williams

Pourrier

McAfee

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Diastolic dysfunction can lead to heart failure with preserved ejection fraction, for which there is no effective therapeutic. Ranolazine has been reported to reduce diastolic dysfunction, but the specific mechanisms of action are unclear. The effect of ranolazine on diastolic function was examined in spontaneously hypertensive rats (SHRs), where left ventricular relaxation is impaired and stiffness increased. The objective of this study was to determine whether ranolazine improves diastolic function in SHRs and identify the mechanism(s) by which improvement is achieved. Specifically, to test the hypothesis that ranolazine, by inhibiting late sodium current, reduces Ca(2+) overload and promotes ventricular relaxation and reduction in diastolic stiffness, the effects of ranolazine or vehicle on heart function and the response to dobutamine challenge were evaluated in aged male SHRs and Wistar-Kyoto rats by echocardiography and pressure-volume loop analysis. The effects of ranolazine and the more specific sodium channel inhibitor tetrodotoxin were determined on the late sodium current, sarcomere length, and intracellular calcium in isolated cardiomyocytes. Ranolazine reduced the end-diastolic pressure-volume relationship slope and improved diastolic function during dobutamine challenge in the SHR. Ranolazine and tetrodotoxin also enhanced cardiomyocyte relaxation and reduced myoplasmic free Ca(2+) during diastole at high-stimulus rates in the SHR. The density of the late sodium current was elevated in SHRs. In conclusion, ranolazine was effective in reducing diastolic dysfunction in the SHR. Its mechanism of action, at least in part, is consistent with inhibition of the increased late sodium current in the SHR leading to reduced Ca(2+) overload.

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“…The healthy left ventricle functions as a 'vacuum cleaner' that prevents LA hypertension by enhancing suction in response to increases in venous return, as with exercise. 51,[66][67][68][69][70][71] This role is achieved through the generation of intraventricular pressure gradients that are determined by the speed of relaxation, the extent and velocity of mitral annular longitudinal motion, the LV 'untwisting' that occurs during early diastole, and the end-systolic volume (ESV) achieved in the preceding contraction cycle (reduced ESV below the equilibrium volume increases recoil to enhance filling, like a compressed spring). 51,72,73 Studies have shown that each of these components is impaired in patients with HFpEF, particularly during the stress of exercise, such that the left ventricle can fill only at the expense of left atrial hypertension.…”

Section: Pathophysiological Components Of Hfpefmentioning

confidence: 99%

“…51,72,73 Studies have shown that each of these components is impaired in patients with HFpEF, particularly during the stress of exercise, such that the left ventricle can fill only at the expense of left atrial hypertension. 17,24,33,70,71 In other words, although the healthy left ventricle effectively pulls in blood during early diastole, [66][67][68] in patients with HFpEF, filling is reliant on high LA pressure to push blood into the chamber (Figure 1). 28,29,33,68,69 Ventricular passive diastolic stiffness is also an important determinant of the increase in LV filling pressures in HFpEF.…”

Section: Pathophysiological Components Of Hfpefmentioning

confidence: 99%

The pathophysiology of heart failure with preserved ejection fraction

2014

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Approximately half of all patients with heart failure have preserved ejection fraction (HFpEF) and, as life expectancies continue to increase in western societies, the prevalence of HFpEF will continue to grow. In contrast to heart failure with reduced ejection fraction (HFrEF), no treatment has been proven in pivotal clinical trials to be effective for HFpEF, largely because of the pathophysiological heterogeneity that exists within the broad spectrum of HFpEF. This syndrome was historically considered to be caused exclusively by left ventricular diastolic dysfunction, but research has identified several other contributory factors, including limitations in left ventricular systolic reserve, systemic and pulmonary vascular function, nitric oxide bioavailability, chronotropic reserve, right heart function, autonomic tone, left atrial function, and peripheral impairments. Multiple individual mechanisms frequently coexist within the same patient to cause symptomatic heart failure, but between patients with HFpEF the extent to which each component is operative can differ widely, confounding treatment approaches. This Review focuses on our current understanding of the pathophysiological mechanisms underlying HFpEF, and how they might be mechanistically related to typical risk factors for HFpEF, including ageing, obesity, and hypertension.

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Loss of Adrenergic Augmentation of Diastolic Intra-LV Pressure Difference in Patients With Diastolic Dysfunction

Abstract: In patients with preserved EF, DD is associated with a reduced adrenergic augmentation of the IVPD from the mid-LV to the LV apex, reflecting less apical suction.

Cited by 58 publications

References 38 publications

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right Ventricular

Enhanced Pulmonary Vasodilator Reserve and Abnormal Right Ventricular

Ranolazine improves diastolic function in spontaneously hypertensive rats

The pathophysiology of heart failure with preserved ejection fraction

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